PROJECT SUMMARY This application seeks support to investigate the neurodevelopmental origins and etiology of major depressive disorder. Specifically, we propose to test a fetal programming model of depression in which adverse conditions during the fetal period-as indicated by exposure to maternal hypothalamic-pituitary-adrenal (HPA) hormones, elevated maternal pro-inflammatory cytokines; early social adversity; and genetic susceptibility, combine to contribute to a trajectory of elevated lifetime risk for major depression. This project also addresses the challenge of health disparities, which for depression are marked and persistent, and which remain an NIH priority area. We propose that the social origins of depression are, in part, neurodevelopmental in nature, and that understanding the developmental pathways to depression will not only yield significant insights into etiology, but will also advance the objective of reducing disparities. The aims of this proposal are: 1) to investigate the combined influences of atypical fetal stress-response pathways and social adversity in relation to the lifetime risk of major depressive disorder; and 2) to investigate gene-environment interactions during the prenatal period in the development of depression. The following hypotheses will be tested. 1) The long-term impact of prenatal risks-as indicated by maternal pro- inflammatory cytokines and maternal HPA activity-for major depression will be heightened under adverse social conditions. Hypothesis 1a is that the combination of maternal-fetal stress, as indicated by elevated levels of inflammatory cytokines (IL-1, IL-6, TNF-) during mid-gestation, and social adversity will be associated with an increased lifetime risk and recurrence of major depression. Hypothesis 1b is that levels of HPA hormones (increased CRH and decreased DHEAS and hCG) during mid-gestation will be associated with the lifetime risk and recurrence of major depression most strongly among individuals born in the context of social adversity 2) Social adversity during pregnancy and early infancy, in combination with genetic susceptibility to depression, with be associated with an elevated lifetime risk of depression. Hypothesis 2 is that polymorphisms in genes associated with HPA circuitry and in genes with prior replicated evidence of environmentally dependent effects on depression, will be associated with an increased risk of depression most strongly among children born in the context of social adversity. This proposal involves data from a 50-year investigation of a well-established birth cohort, the New England Family Study, which is uniquely capable of addressing the prenatal determinants of mental illness. The applicant is a social epidemiologist whose long-term career objectives are to discover the developmental pathways leading to major depression, and to identify modifiable pathways in order to reduce the public health burden of depression.